EP3107908B1 - Dérivés de l'acide pyridin-3-yl-acétique utilisés comme inhibiteurs de la réplication du virus de l'immunodéficience humaine - Google Patents

Dérivés de l'acide pyridin-3-yl-acétique utilisés comme inhibiteurs de la réplication du virus de l'immunodéficience humaine Download PDF

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EP3107908B1
EP3107908B1 EP15709381.6A EP15709381A EP3107908B1 EP 3107908 B1 EP3107908 B1 EP 3107908B1 EP 15709381 A EP15709381 A EP 15709381A EP 3107908 B1 EP3107908 B1 EP 3107908B1
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Prior art keywords
butoxy
tert
phenyl
dimethylpyridin
acetic acid
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EP3107908A1 (fr
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B. Narasimhulu Naidu
Manoj Patel
Jeffrey Lee Romine
Denis R. St. Laurent
Tao Wang
Zhongxing Zhang
John F. Kadow
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ViiV Healthcare UK No 5 Ltd
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ViiV Healthcare UK No 5 Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/61—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the disclosure generally relates to compounds, compositions, and methods for the treatment of human immunodeficiency virus (HIV) infection.
  • HIV human immunodeficiency virus
  • the disclosure provides novel inhibitors of HIV, pharmaceutical compositions containing such compounds, and methods for using these compounds in the treatment of HIV infection.
  • HIV Human immunodeficiency virus
  • AIDS acquired immune deficiency syndrome
  • antiviral drugs available to combat the infection. These drugs can be divided into classes based on the viral protein they target or their mode of action. In particular, saquinavir, indinavir, ritonavir, nelfinavir atazanavir darunavir, amprenavir, fosamprenavir, lopinavir and tipranavir are competitive inhibitors of the aspartyl protease expressed by HIV.
  • Zidovudine, didanosine, stavudine, lamivudine, zalcitabine, emtricitibine, tenofovir and abacavir are nucleos(t)ide reverse transcriptase inhibitors that behave as substrate mimics to halt viral cDNA synthesis.
  • the non-nucleoside reverse transcriptase inhibitors nevirapine, delavirdine, efavirenz and etravirine inhibit the synthesis of viral cDNA via a non-competitive (or uncompetitive) mechanism.
  • Enfuvirtide and maraviroc inhibit the entry of the virus into the host cell.
  • HIV integrase inhibitor MK-0518, Isentress®
  • Isentress® An HIV integrase inhibitor, raltegravir (MK-0518, Isentress®), has also been approved for use in treatment experienced patients, and it is clear that this class of inhibitors is very effective as part of a combination regimen containing HIV inhibitors of different classes.
  • the invention provides technical advantages, for example, the compounds are novel and are useful in the treatment of HIV. Additionally, the compounds provide advantages for pharmaceutical uses, for example, with regard to one or more of their mechanism of action, binding, inhibition efficacy, target selectivity, solubility, safety profiles, or bioavailability.
  • the invention encompasses compounds of Formula I including pharmaceutically acceptable salts, their pharmaceutical compositions, methods for making these compounds and their use in inhibiting HIV integrase and treating those infected with HIV or AIDS.
  • One aspect of the invention is a compound of Formula I where:
  • Another aspect of the invention is a compound of formula I where:
  • R 1 is alkyl
  • R 2 is phenyl or pyridinyl and is substituted with 1 substituent selected from alkoxy, (Ar 1 )O, or (Ar 1 )alkoxy, and is also substituted with 0-3 substituents selected from halo, alkyl, haloalkyl, alkoxy, and haloalkoxy
  • R 3 is piperidinyl substituted with 0-3 alkyl substituents
  • R 4 is alkyl
  • R 5 is alkyl
  • Ar 1 is phenyl substituted with 0-3 substituents selected from halo, alkyl, haloalkyl, alkoxy, and haloalkoxy; or a pharmaceutically acceptable salt thereof.
  • R 2 is phenyl substituted with 1 substituent selected from hydroxy, alkoxy, (Ar 1 )O, and (Ar 1 )alkoxy, (Ar 1 )(alkoxy)alkoxy, and is also substituted with 0-3 substituents selected from halo, alkyl, haloalkyl, alkoxy, and haloalkoxy;
  • R 2 is phenyl substituted with 1 substituent selected from alkoxy, (Ar 1 )O, or (Ar 1 )alkoxy, and is also substituted with 0-3 substituents selected from halo, alkyl, haloalkyl, alkoxy, and haloalkoxy.
  • R 2 is pyridinyl, pyridazinyl, pyrimidinyl, or pyridazinyl, and is substituted with 1 substituent selected from hydroxy, alkoxy, (Ar 1 )O, and (Ar 1 )alkoxy, (Ar 1 )(alkoxy)alkoxy, and is also substituted with 0-3 substituents selected from halo, alkyl, haloalkyl, alkoxy, and haloalkoxy.
  • R 3 is piperidinyl, substituted with 0-3 substituents selected from cyano, halo, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkenyl, alkoxy, haloalkoxy, CON(R 6 )(R 7 ), phenyl, benzyl, or (alkyl)oxadiazolyl.
  • R 3 is piperidinyl, gem-disubstituted in the 4-position with 2 substituents selected from cyano, halo, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkenyl, alkoxy, haloalkoxy, CON(R 6 )(R 7 ), phenyl, benzyl, or (alkyl)oxadiazolyl.
  • R 1 is hydrogen or alkyl
  • R 2 is halo
  • R 3 is halo
  • R 5 is hydrogen or alkyl
  • R 6 is alkyl
  • R 1 is hydrogen or alkyl
  • R 2 is halo
  • R 3 is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, homopiperidinyl, homopiperazinyl, or homomorpholinyl, and is substituted with 0-3 substituents selected from halo, alkyl, haloalkyl, alkoxy, cyano, and haloalkoxy
  • R 5 is hydrogen or alkyl
  • R 6 is alkyl.
  • R 1 is hydrogen or alkyl
  • R 2 is halo
  • R 3 is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, homopiperidinyl, homopiperazinyl, or homomorpholinyl, and is substituted with 0-3 substituents selected from halo, alkyl, haloalkyl, alkoxy, cyano, and haloalkoxy
  • R 4 is hydrogen or alkyl
  • R 5 is hydrogen or alkyl
  • R 6 is alkyl.
  • variable substituent including R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and Ar 1 can be used independently with the scope of any other instance of a variable substituent.
  • the invention includes combinations of the different aspects, as long as included in the claims.
  • Alkyl means a straight or branched alkyl group composed of 1 to 6 carbons.
  • Alkenyl means a straight or branched alkyl group composed of 2 to 6 carbons with at least one double bond.
  • Alkynyl means a straight or branched alkyl group composed of 2 to 6 carbons with at least one triple bond.
  • Cycloalkyl means a monocyclic ring system composed of 3 to 7 carbons.
  • Cycloalkenyl means a monocyclic ring system composed of 4 to 7 carbons.
  • Halo means fluoro, chloro, bromo, or iodo.
  • Haloalkyl and haloalkoxy include all halogenated isomers from monohalo to perhalo.
  • Aryl includes carbocyclic and heterocyclic aromatic substituents. Terms with a hydrocarbon moiety (e.g. alkoxy) include straight and branched isomers for the hydrocarbon portion. Parenthetic and multiparenthetic terms are intended to clarify bonding relationships to those skilled in the art. For example, a term such as ((R)alkyl) means an alkyl substituent further substituted with the substituent R.
  • the invention includes all pharmaceutically acceptable salt forms of the compounds.
  • Pharmaceutically acceptable salts are those in which the counter ions do not contribute significantly to the physiological activity or toxicity of the compounds and as such function as pharmacological equivalents. These salts can be made according to common organic techniques employing commercially available reagents. Some anionic salt forms include acetate, acistrate, besylate, bromide, chloride, citrate, fumarate, glucouronate, hydrobromide, hydrochloride, hydroiodide, iodide, lactate, maleate, mesylate, nitrate, pamoate, phosphate, succinate, sulfate, tartrate, tosylate, and xinofoate.
  • Some cationic salt forms include ammonium, aluminum, benzathine, bismuth, calcium, choline, diethylamine, diethanolamine, lithium, magnesium, meglumine, 4-phenylcyclohexylamine, piperazine, potassium, sodium, tromethamine, and zinc.
  • the invention includes all stereoisomeric forms of the compounds including enantiomers and diastereomers. Methods of making and separating stereoisomers are known in the art.
  • the invention includes all tautomeric forms of the compounds.
  • the invention includes atropisomers and rotational isomers.
  • the invention is intended to include all isotopes of atoms occurring in the present compounds.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include deuterium and tritium.
  • Isotopes of carbon include 13 C and 14 C.
  • Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed. Such compounds may have a variety of potential uses, for example as standards and reagents in determining biological activity. In the case of stable isotopes, such compounds may have the potential to favorably modify biological, pharmacological, or pharmacokinetic properties.
  • a recombinant NL-RLuc proviral clone was constructed in which a section of the nef gene from NL4-3 was replaced with the Renilla Luciferase gene. This virus is fully infectious and can undergo multiple cycles of replication in cell culture.
  • the luciferous reporter provides a simple and easy method for quantitating the extent of virus growth and consequently, the antiviral activity of test compounds.
  • the plasmid pNLRLuc contains the proviral NL-Rluc DNA cloned into pUC18 at the Pvu II site.
  • the NL-RLuc virus was prepared by transfection of 293T cells with the plasmid pNLRLuc.
  • Transfections were performed using the LipofectAMINE PLUS kit from Invitrogen (Carlsbad, CA) according to the manufacturer and the virus generated was titered in MT-2 cells.
  • the titrated virus was used to infect MT-2 cells in the presence of compound, and after 5 days of incubation, cells were processed and quantitated for virus growth by the amount of expressed luciferase.
  • Assay media was RPMI 1640 supplemented with 10% heat inactivated fetal bovine serum (FBS), 100 units/ml penicillin G/100 units/ml streptomycin, 10 mM HEPES buffer pH 7.55 and 2 mM L-glutamine. The results from at least 2 experiments were used to calculate the EC 50 values.
  • Example EC 50 ⁇ M Example EC 50 ⁇ M 1 0.037 42 0.004 2 0.012 43 0.014 3 0.02 44 0.012 4 0.012 45 0.029 5 0.011 46 0.014 6 0.02 47 0.018 7 0.009 48 0.001 8 0.011 49 0.034 9 0.009 50 0.003 10 0.027 51 0.006 11 0.004 52 0.005 12 0.005 53 0.002 13 0.012 54 0.008 14 0.028 55 0.093 15 0.004 56 0.002 16 0.172 57 0.217 17 0.004 58 0.009 18 0.002 59 0.021 19 0.012 60 0.262 20 0.003 61 0.044 21 0.014 62 0.166 22 0.007 63 0.119 23 0.005 64 0.026 24 0.003 65 0.044 25 0.003 66 0.141 26 0.017 67 0.007 27 0.012 68 0.042 28 0.019 69 1.994 29 0.015 70 3.051 30 0.006
  • Another disclosure of the invention is a method for treating HIV infection in a human patient comprising administering a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable carrier.
  • Another aspect of the invention is the use of a compound of formula I in the manufacture of a medicament for the treatment of AIDS or HIV infection.
  • Another disclosure of the invention is a method for treating HIV infection in a human patient comprising the administration of a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, with a therapeutically effective amount of at least one other agent used for treatment of AIDS or HIV infection selected from the group consisting of nucleoside HIV reverse transcriptase inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, HIV protease inhibitors, HIV fusion inhibitors, HIV attachment inhibitors, CCR5 inhibitors, CXCR4 inhibitors, HIV budding or maturation inhibitors, and HIV integrase inhibitors.
  • Another disclosure of the invention is a method wherein the agent is a nucleoside HIV reverse transcriptase inhibitor.
  • nucleoside HIV reverse transcriptase inhibitor is selected from the group consisting of abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine, and zidovudine, or a pharmaceutically acceptable salt thereof.
  • Another disclosure of the invention is a method wherein the agent is a non-nucleoside HIV reverse transcriptase inhibitor.
  • non-nucleoside HIV reverse transcriptase inhibitor is selected from the group consisting of delavirdine, efavirenz, and nevirapine, or a pharmaceutically acceptable thereof.
  • Another disclosure of the invention is a method wherein the agent is an HIV protease inhibitor.
  • HIV protease inhibitor is selected from the group consisting of amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir and fosamprenavir, or a pharmaceutically acceptable salt thereof.
  • Another disclosure of the invention is a method wherein the agent is an HIV fusion inhibitor.
  • Another disclosureof the invention is a method wherein the HIV fusion inhibitor is enfuvirtide or T-1249, or a pharmaceutically acceptable salt thereof.
  • Another disclosure of the invention is a method wherein the agent is an HIV attachment inhibitor.
  • Another disclosuret of the invention is a method wherein the agent is a CCR5 inhibitor.
  • Another disclosure of the invention is a method wherein the CCR5 inhibitor is selected from the group consisting of Sch-C, Sch-D, TAK-220, PRO-140, and UK-427,857 , or a pharmaceutically acceptable salt thereof.
  • Another disclosure of the invention is a method wherein the agent is a CXCR4 inhibitor.
  • Another disclosureof the invention is a method wherein the CXCR4 inhibitor is AMD-3100, or a pharmaceutically acceptable salt thereof.
  • Another disclosureof the invention is a method wherein the agent is an HIV budding or maturation inhibitor.
  • disclosure of the invention is a method wherein the budding or maturation inhibitor is PA-457, or a pharmaceutically acceptable salt thereof.
  • Another disclosure of the invention is a method wherein the agent is an HIV integrase inhibitor.
  • Another aspect of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, with at least one other agent used for treatment of AIDS or HIV infection selected from the group consisting of nucleoside HIV reverse transcriptase inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, HIV protease inhibitors, HIV fusion inhibitors, HIV attachment inhibitors, CCR5 inhibitors, CXCR4 inhibitors, HIV budding or maturation inhibitors, and HIV integrase inhibitors, and a pharmaceutically acceptable carrier.
  • at least one other agent used for treatment of AIDS or HIV infection selected from the group consisting of nucleoside HIV reverse transcriptase inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, HIV protease inhibitors, HIV fusion inhibitors, HIV attachment inhibitors, CCR5 inhibitors, CXCR4 inhibitors, HIV budding or maturation inhibitors, and HIV integrase inhibitors,
  • composition wherein the agent is a nucleoside HIV reverse transcriptase inhibitor.
  • nucleoside HIV transcriptase inhibitor is selected from the group consisting of abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine, and zidovudine, or a pharmaceutically acceptable salt thereof.
  • composition wherein the agent is a non-nucleoside HIV reverse transcriptase inhibitor.
  • composition wherein the non-nucleoside HIV reverse transcriptase inhibitor is selected from the group consisting of delavirdine, efavirenz, and nevirapine, or a pharmaceutically acceptable salt thereof.
  • composition wherein the agent is an HIV protease inhibitor.
  • composition wherein the HIV protease inhibitor is selected from the group consisting of amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir and fosamprenavir, or a pharmaceutically acceptable salt thereof.
  • composition wherein the agent is an HIV fusion inhibitor.
  • composition wherein the HIV fusion inhibitor is enfuvirtide or T-1249, or a pharmaceutically acceptable salt thereof.
  • composition wherein the agent is an HIV attachment inhibitor.
  • composition wherein the agent is a CCR5 inhibitor.
  • composition wherein the CCR5 inhibitor is selected from the group consisting of Sch-C, Sch-D, TAK-220, PRO-140, and UK-427,857 , or a pharmaceutically acceptable salt thereof.
  • composition wherein the agent is a CXCR4 inhibitor.
  • composition wherein the CXCR4 inhibitor is AMD-3100 or a pharmaceutically acceptable salt thereof.
  • composition wherein the agent is an HIV budding or maturation inhibitor.
  • composition wherein the budding or maturation inhibitor is PA-457, or a pharmaceutically acceptable salt thereof.
  • composition wherein the agent is an HIV integrase inhibitor.
  • Combination means that the components are part of a combination antiretroviral therapy or highly active antiretroviral therapy (HAART) as understood by practitioners in the field of AIDS and HIV infection.
  • HAART highly active antiretroviral therapy
  • “Therapeutically effective” means the amount of agent required to provide a meaningful patient benefit as understood by practitioners in the field of AIDS and HIV infection. In general, the goals of treatment are suppression of viral load, restoration and preservation of immunologic function, improved quality of life, and reduction of HIV-related morbidity and mortality.
  • Patient means a person infected with the HIV virus and suitable for therapy as understood by practitioners in the field of AIDS and HIV infection.
  • compositions comprised of a therapeutically effective amount of a compound of Formula I or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier and may contain conventional excipients.
  • a therapeutically effective amount is that which is needed to provide a meaningful patient benefit.
  • Pharmaceutically acceptable carriers are those conventionally known carriers having acceptable safety profiles.
  • Compositions encompass all common solid and liquid forms including capsules, tablets, losenges, and powders as well as liquid suspensions, syrups, elixers, and solutions. Compositions are made using common formulation techniques, and conventional excipients (such as binding and wetting agents) and vehicles (such as water and alcohols) are generally used for compositions. See, for example, Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, PA (1985 ).
  • Solid compositions are normally formulated in dosage units and compositions providing from about 1 to 1000 mg of the active ingredient per dose are preferred. Some examples of dosages are 1 mg, 10 mg, 100 mg, 250 mg, 500 mg, and 1000 mg. Generally, other antiretroviral agents will be present in a unit range similar to agents of that class used clinically. Typically, this is 0.25-1000 mg/unit.
  • Liquid compositions are usually in dosage unit ranges. Generally, the liquid composition will be in a unit dosage range of 1-100 mg/mL. Some examples of dosages are 1 mg/mL, 10 mg/mL, 25 mg/mL, 50 mg/mL, and 100 mg/mL. Generally, other antiretroviral agents will be present in a unit range similar to agents of that class used clinically. Typically, this is 1-100 mg/mL.
  • the invention encompasses all conventional modes of administration; oral and parenteral methods are preferred.
  • the dosing regimen will be similar to other antiretroviral agents used clinically.
  • the daily dose will be 1-100 mg/kg body weight daily.
  • more compound is required orally and less parenterally.
  • the specific dosing regimen will be determined by a physician using sound medical judgment.
  • the invention also encompasses the compounds for use in methods where the compound is given in combination therapy. That is, the compound can be used in conjunction with, but separately from, other agents useful in treating AIDS and HIV infection. Some of these agents include HIV attachment inhibitors, CCR5 inhibitors, CXCR4 inhibitors, HIV cell fusion inhibitors, HIV integrase inhibitors, HIV nucleoside reverse transcriptase inhibitors, HIV non-nucleoside reverse transcriptase inhibitors, HIV protease inhibitors, budding and maturation inhibitors, immunomodulators, and antiinfectives.
  • the compound of Formula I will generally be given in a daily dose of 1-100 mg/kg body weight daily in conjunction with other agents.
  • the other agents generally will be given in the amounts used therapeutically.
  • the specific dosing regimen will be determined by a physician using sound medical judgment.
  • the compounds of this invention can be made by various methods known in the art including those of the following schemes and in the specific embodiments section.
  • the structure numbering and variable numbering shown in the synthetic schemes are distinct from, and should not be confused with, the structure or variable numbering in the claims or the rest of the specification.
  • the variables in the schemes are meant only to illustrate how to make some of the compounds of this invention.
  • Intermediates I-10 are conveniently transformed to intermediates II-2 using conditions well-known in the art, including but not limited to the Suzuki coupling between intermediates I-10 and II-1. Cleavage of protecting group in II-2 provided phenol II-3. Alkylation of the phenol II-3 was achieved by using conditions well known to those skilled in the art, including but not limited to Mitshunobu reaction to provide the intermediate II-4. Hydrolysis of intermediate II-4 by using conditions well-known in the literature furnished carboxylic acid II-5.
  • Triethylamine 28.8 mL, 206 mmol was added to a nitrogen purged solution of 3,5-dibromo-2,6-dimethylpyridin-4-ol (58 g, 206 mmol) and phosphorous oxychloride (57.7 mL, 619 mmol) in chloroform (450 mL) and stirred for 1 h at rt, then 3 h at 80 °C. The reaction was removed from heating and immediately concentrated under house vaccum; then under high vacuum.
  • the homogeneous brown reaction mixture was rapidly transferred via cannula to a solution of ethyl 2-chloro-2-oxoacetate (6.14 ml, 54.9 mmol, degassed for 5 min by bubbling N2 through the solution) in THF (50 mL) maintained at -30 °C.
  • the resulting reaction mixture was stirred (1.5 h) while warming to 0 °C.
  • taken up in to Et 2 O (200 mL) washed with 1:1 sat Na 2 CO 3 /1M NH 4 Cl (3 x 50 mL), dried (MgSO 4 ), filtered and concentrated to give brown viscous oil.
  • reaction mixture was slowly warmed to -15 °C over 1 h and then left for 2 h at -15 °C. Then, diluted with EtOAc (100 mL), washed with sat Na 2 CO 3 (4 x 25 mL) by vigorously stirring and separating aqueous layers.
  • reaction mixture was concentrated and purified by prep-HPLC to afford (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-(3-(4-fluorophenyl)propoxy)phenyl)-2,6-dimethylpyridin-3-yl)acetate (0.0351 g, 0.058 mmol, 68.0 % yield) as glassy solid.
  • reaction mixture was concentrated and purified by prep-HPLC to afford (S)-ethyl 2-(tert-butoxy)-2-(5-(4-(3,3-dimethylbutoxy)phenyl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetate (0.0205 g, 0.037 mmol, 41.4 % yield) as white solid.
  • the propan-2-ol (38.2 mL, 499 mmol) was added drop wise over 15 min to a cold (0 °C), nitrogen purged solution of oxalyl dichloride (101 g, 799 mmol) and the reaction was stirred at room temperature for 2.5 h. Then a reflux condenser was fitted and a slight vacuum was applied for about 1 h until HCl gas was removed (the HCl was trapped in by a sat'd solution of NaHCO 3 ). The reflux condenser was removed and the flask was fitted with a short path distillation head.
  • reaction mixture was transferred via cannula into a 1 L RB-flask containing isopropyl 2-chloro-2-oxoacetate (26.6 g, 176 mmol) in THF (160 mL) maintained at - 60 °C, and the reaction stirred an additional 2.5 h while being allowed to warm to - 10 °C.
  • the reaction was quenched upon diluted with a mixture of 10% NH 4 Cl solution (80 mL) in ether (320 mL). The organic layer was washed with 160 mL of sat'd NaHCO 3 /10% NH 4 Cl solution (1:1), brine, and dried (Na 2 SO 4 ).
  • reaction mixture was slowly warmed to -30 °C over 1 h and left in refrigerator (-20 °C) for 3 days. Then, the reaction mixture was diluted with EtOAc (100 mL) and 20 mL of 1M Na 2 CO 3 , and vigorously stirred for 30 min.
  • reaction mixture was cooled down to -30 °C and bubbled isobutene ( ⁇ 15 min). After 24 h, reaction mixture was neutralized with sat. Na 2 CO 3 (20 mL), organic layer separated and aqueous layer was extracted with CH 2 Cl 2 (25 mL).
  • PdOAc2 (0.048 g, 0.213 mmol) was added, degassed for 5 min and mixture was heated at 80°C for 3 h. After cooling to room temp, water was added and the mixture was extracted with ethyl acetate, washed with brine, dried (Na 2 SO 4 ), filrered and concentrated.
  • the isobutylene gas was bubbled into a nitrogen purged, cooled (0 °C) solution of (2S)-isopropyl 2-(5-bromo-4-(3-cyclopropylpyrrolidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-hydroxyacetate (525 mg, 1.28 mmol) and 0.15 mL of 70% HClO 4 in DCM (10 mL) for 20 min.
  • the reaction mixture was allowed to warm to rt and stirred for 18 h in a pressure sealed vessel, diluted with DCM, washed with 1M Na 2 CO 3 solution, and dried over MgSO 4 .
  • the Pd(Ph 3 P) 4 (61.8 mg, 0.053 mmol) was added to a nitrogen purged and degassed solution of (2S)-isopropyl 2-(5-bromo-4-(3-cyclopropylpyrrolidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate (125 mg, 0.27 mmol), (4-(4-fluorophenethoxy)phenyl)boronic acid (77 mg, 0.29 mmol), and potassium phosphate tribasic (397 mg, 1.9 mmol) in 1,4-dioxane (3.5 mL) and water (0.9 mL).
  • the isobutylene gas was bubbled into a nitrogen purged, cooled (0 °C) solution of (S)-isopropyl 2-(5-bromo-4-(3,3-difluoroazetidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-hydroxyacetate (175 mg, 0.45 mmol) and 0.05 mL of 70% HClO 4 in DCM (5 mL) for 20 min.
  • the reaction mixture was allowed to warm to rt and stirred for 18 h in a pressure sealed vessel, diluted with DCM, washed with 1M Na 2 CO 3 solution, and dried over MgSO 4 .
  • the isobutylene gas was bubbled into a nitrogen purged, cooled (0 °C) solution of (S)-isopropyl 2-(5-bromo-4-(3,3-dimethylazetidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-hydroxyacetate (970 mg, 2.5 mmol) and 0.5 mL of 70% HClO 4 in DCM (20 mL) for 20 min.
  • the reaction mixture was allowed to warm to rt and stirred for 18 h in a pressure sealed vessel, diluted with DCM, washed with 1M Na 2 CO 3 solution, and dried over MgSO 4 .
  • the Pd(Ph 3 P) 4 (57.6 mg, 0.05 mmol) was added to a nitrogen purged and degassed solution of (S)-isopropyl 2-(5-bromo-4-(3,3-dimethylazetidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate (110 mg, 0.25 mmol), (4-(4-fluorophenethoxy)phenyl)boronic acid (71.3 mg, 0.27 mmol), and sodium carbonate (185 mg, 1.74 mmol) in dioxane (3 mL) and water (0.6 mL) and stirred in a screw-capped pressure vessel for 4 h at 90 °C.
  • the isobutylene gas was bubbled into a nitrogen purged, cooled (0 °C) solution of (S)-isopropyl 2-(5-bromo-4-(3-isopropylazetidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-hydroxyacetate (601 mg, 1.5 mmol) and 0.5 mL of 70% HClO 4 in DCM (12 mL) for 20 min.
  • the reaction mixture was allowed to warm to rt and stirred for 18 h in a pressure sealed vessel, diluted with DCM, washed with 1M Na 2 CO 3 solution, and dried over MgSO 4 .
  • the Pd(Ph 3 P) 4 (38.1 mg, 0.033 mmol) was added to a nitrogen purged and degassed solution of (S)-isopropyl 2-(5-bromo-4-(3-isopropylazetidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate (150 mg, 0.33 mmol), (4-(4-fluorophenethoxy)phenyl)boronic acid (94 mg, 0.36 mmol), and sodium carbonate (209 mg, 1.98 mmol) in dioxane (4.5 mL) and water (0.9 mL) and stirred in a screw-capped pressure vessel for 4 h at 90 °C.
  • the isobutylene gas was bubbled into a nitrogen purged, cooled (0 °C) solution of (S)-isopropyl 2-(5-bromo-2,6-dimethyl-4-(4-phenylpiperidin-1-yl)pyridin-3-yl)-2-hydroxyacetate (1.95 g, 1.5 mmol) and 0.6 mL of 70% HClO 4 in DCM (25 mL) for 20 min.
  • the reaction mixture was allowed to warm to rt and stirred for 18 h in a pressure sealed vessel, diluted with DCM, washed with 1M Na 2 CO 3 solution, and dried over MgSO 4 .
  • the Pd(Ph 3 P) 4 (33.5 mg, 0.029 mmol) was added to a nitrogen purged and degassed solution of (S)-isopropyl 2-(5-bromo-2,6-dimethyl-4-(4-phenylpiperidin-1-yl)pyridin-3-yl)-2-(tert-butoxy)acetate (150 mg, 0.29 mmol), (4-(4-fluorophenethoxy)phenyl)boronic acid (83 mg, 0.32 mmol), and sodium carbonate (184 mg, 1.74 mmol) in dioxane (4.5 mL) and water (0.9 mL) and stirred in a screw-capped pressure vessel for 4 h at 90 °C.
  • the isobutylene gas was bubbled into a nitrogen purged, cooled (0 °C) solution of (S)-isopropyl 2-(5-bromo-4-(4-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-hydroxyacetate (540 g, 1.1 mmol) and 0.15 mL of 70% HClO 4 in DCM (8 mL) for 20 min. The reaction mixture was allowed to warm to rt and stirred for 18 h in a pressure sealed vessel, diluted with DCM, washed with 1M Na 2 CO 3 solution, and dried over Na 2 SO 4 .
  • the isobutylene gas was bubbled into a nitrogen purged, cooled (0 °C) solution of 2-(5-bromo-2,6-dimethyl-4-(4-(trifluoromethyl)piperidin-1-yl)pyridin-3-yl)-2-hydroxyacetate (1.9 g, 4.19 mmol) and 0.4 mL of 70% HClO 4 in DCM (20 mL) for 20 min.
  • the reaction mixture was allowed to warm to rt and stirred for 18 h in a pressure sealed vessel, after which it was recooled, and an additional 0.4 mL of 70% HClO 4 was added, and the reaction stirred for 24 h at rt.
  • the isobutylene gas was bubbled into a nitrogen purged, cooled (0 °C) solution of (S)-isopropyl 2-(5-bromo-4-(4-ethyl-4-methylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-hydroxyacetate (1.9 g, 4.19 mmol) and 0.6 mL of 70% HClO 4 in DCM (15 mL) for 20 min.
  • the reaction mixture was allowed to warm to rt and stirred for 18 h in a pressure sealed vessel, after which it was recooled, and an additional 0.4 mL of 70% HClO 4 was added at 0 °C, and the reaction was stirred for 24 h at rt.
  • the Pd(Ph 3 P) 4 (71 mg, 0.062 mmol) was added to a nitrogen purged and degassed solution of (S)-isopropyl 2-(5-bromo-2,6-dimethyl-4-(4-phenylpiperidin-1-yl)pyridin-3-yl)-2-(tert-butoxy)acetate (150 mg, 0.31 mmol), (4-(4-fluorophenethoxy)phenyl)boronic acid (89 mg, 0.34 mmol), and potassium phosphate tribasic (494 mg, 2.3 mmol) in dioxane (2 mL) and water (1.25 mL) and stirred in a screw-capped pressure vessel for 24 h at 80 °C.
  • the isobutylene gas was bubbled into a nitrogen purged, cooled (0 °C) solution of (S)-isopropyl 2-(5-bromo-2,6-dimethyl-4-(4-methylpiperidin-1-yl)pyridin-3-yl)-2-hydroxyacetate (2.25 g, 5.63 mmol) and 0.53 mL of 70% HClO 4 in DCM (30 mL) for 20 min.
  • the reaction mixture was allowed to warm to rt and stirred for 72 h in a pressure sealed vessel.
  • the reaction was then diluted with DCM, washed with 1M Na 2 CO 3 solution, and dried over MgSO 4 .
  • the isobutylene gas was bubbled into a nitrogen purged, cooled (0 °C) solution of (S)-isopropyl 2-(5-bromo-4-(4-methoxy-4-methylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-hydroxyacetate (1.45 g, 3.38 mmol) and 0.32 mL of 70% HClO 4 in DCM (30 mL) for 20 min.
  • the reaction mixture was allowed to warm to rt and stirred for 48 h in a pressure sealed vessel.
  • the reaction was then diluted with DCM, washed with 1M Na 2 CO 3 solution, and dried over MgSO 4 .
  • the isobutylene gas was bubbled into a nitrogen purged, cooled (0 °C) solution of (S)-isopropyl 2-(5-bromo-4-(4-cyano-4-methylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-hydroxyacetate (670 mg, 1.58 mmol) and 0.15 mL of 70% HClO 4 in DCM (15 mL) for 20 min. The reaction mixture was allowed to warm to rt and stirred for 48 h in a pressure sealed vessel. The reaction was then diluted with DCM, washed with 1M Na 2 CO 3 solution, and dried over MgSO 4 .
  • Pd(Ph 3 P) 4 (144 mg, 0.125 mmol) was added to an argon-degassed solution (S)-isopropyl 2-(5-bromo-4-(4-cyano-4-methylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate (300 mg, 0.624 mmol), 2-(4-(4-fluorophenethoxy)phenyl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione (179 mg, 0.687 mmol), potassium phosphate tribasic (994 mg, 4.68 mmol) in dioxane (4 ml) and water (0.8 ml) stirred in a screw-capped pressure vessel for 16 h at 90 °C.
  • the isobutylene gas was bubbled into a nitrogen purged, cooled (0 °C) solution of (S)-isopropyl 2-(5-bromo-2,6-dimethyl-4-(4-(propan-2-ylidene)piperidin-1-yl)pyridin-3-yl)-2-hydroxyacetate (1.0 g, 2.3 mmol) and 0.30 mL of 70% HClO 4 in DCM (30 mL) for 20 min. The reaction mixture was allowed to warm to rt and stirred for 48 h in a pressure sealed vessel. The reaction was then diluted with DCM, washed with 1M Na 2 CO 3 solution, and dried over MgSO 4 .
  • the isobutylene gas was bubbled into a nitrogen purged, cooled (0 °C) solution of (S)-isopropyl 2-(4-(4-benzylpiperidin-1-yl)-5-bromo-2,6-dimethylpyridin-3-yl)-2-hydroxyacetate (1.35 g, 2.84 mmol) and 0.27 mL of 70% HClO 4 in DCM (25 mL) for 20 min.
  • the reaction mixture was allowed to warm to rt and stirred for 48 h in a pressure sealed vessel.
  • the reaction was then diluted with DCM, washed with 1M Na 2 CO 3 solution, and dried over MgSO 4 .
  • the isobutylene gas was bubbled into a nitrogen purged, cooled (0 °C) solution of (S)-isopropyl 2-(5-bromo-4-(4-fluoro-4-methylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-hydroxyacetate (600 mg, 1.44 mmol) and 0.14 mL of 70% HClO 4 in DCM (15 mL) for 20 min. The reaction mixture was allowed to warm to rt and stirred for 5 days. The reaction was diluted with DCM, washed with 1M Na 2 CO 3 solution, and dried over MgSO 4 .
  • the isobutylene gas was bubbled into a nitrogen purged, cooled (0 °C) solution (S)-isopropyl 2-(5-bromo-4-((3,5-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-hydroxyacetate (710 mg, 1.7 mmol) and 0.17 mL of 70% HClO 4 in DCM (25 mL) for 20 min.
  • the reaction mixture was allowed to warm to rt and stirred for 24 h in a pressure sealed vessel.
  • the reaction was then diluted with DCM, washed with 1M Na 2 CO 3 solution, and dried over MgSO 4 .
  • the diacetoxypalladium (5 mg, 0.021 mmol) was added to an argon purged and degassed solution (S)-isopropyl 2-(5-bromo-4-((3,5-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate (100 mg, 0.213 mmol), 2-(4-(4-fluorophenethoxy)phenyl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione (87 mg, 0.234 mmol), and 2-dicyclohexylphosphino-2',6'-dimethoxy-biphenyl (17.5 mg, 0.043 mmol), and potassium phosphate tribasic (339 mg, 1.6 mmol) in dioxane (3 mL) and water (0.6 mL) and stirred in a screw-capped pressure vessel for 16 h at 90 °C
  • Examples 57-66 were prepared according to the general procedure described below.
  • the potassium hydroxide (72.2 mg, 1.28 mmol) was added to a solution (S)-isopropyl 2-(tert-butoxy)-2-(5-(4-(4-fluorophenethoxy)phenyl)-2,6-dimethyl-4-(4-phenylpiperidin-1-yl)pyridin-3-yl)acetate (84 mg, 0.13 mmol) in ethanol (3 mL) and stirred for 3 h at 90 °C. The reaction mixture was neutralized with IN HCl solution, extracted with EtOAc, and the organic layer was washed with brine, and dried (MgSO 4 ).
  • the potassium hydroxide (54.6 mg, 0.97 mmol) was added to a station (S)-isopropyl 2-(tert-butoxy)-2-(5-(4-(4-fluorophenethoxy)phenyl)-2,6-dimethyl-4-(4-(propan-2-ylidene)piperidin-1-yl)pyridin-3-yl)acetate (60 mg, 0.097 mmol) in ethanol (2 mL) and stirred for 6 h at 90 °C. The reaction mixture was neutralized with IN HCl solution, extracted with EtOAc, and the organic layer was washed with brine, and dried (MgSO 4 ).
  • the potassium hydroxide (86 mg, 1.54 mmol) was added to a station (S)-isopropyl 2-(4-(4-benzylpiperidin-1-yl)-5-(4-(4-fluorophenethoxy)phenyl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate (102 mg, 0.154 mmol) in ethanol (3 mL) and stirred for 12 h at 90 °C. The reaction mixture was neutralized with IN HCl solution, extracted with EtOAc, and the organic layer was washed with brine, and dried (MgSO 4 ).

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Claims (11)

  1. Composé de formule I
    Figure imgb0212
     dans laquelle :
    R1 est un alkyle ;
    R2 est un phényle, pyridinyle, pyrimidinyle ou pyridazinyle, et est substitué par 1 substituant choisi parmi un hydroxy, alkoxy, (Ar1)O, et (Ar1)alkoxy, (Ar1)-(alkoxy)alkoxy, et est aussi substitué par 0 à 3 substituants choisis parmi un halogène, alkyle, halogénoalkyle, alkoxy et halogénoalkoxy ;
    R3 est un azétidinyle, pyrrolidinyle, pipéridinyle, pipérazinyle, morpholinyle, homopipéridinyle, homopipérazinyle, ou homomorpholinyle, et est substitué par 0 à 3 substituants choisis parmi un cyano, halogène, alkyle, halogénoalkyle, cycloalkyle, halogénocycloalkyle, alcényle, alkoxy, halogénoalkoxy, CON(R6)(R7), phényle, benzyle ou (alkyl)oxadiazolyle ;
    R4 est un alkyle ou halogénoalkyle ;
    R5 est un alkyle ;
    R6 est un hydrogène ou alkyle ;
    R7 est un hydrogène ou alkyle ; et
    Ar1 est un phényle, naphtyle, pyrrolyle, furanyle, thiényle, pyrazolyle, isoxazolyle, isothiazolyle, imidazolyle, oxazolyle, thiazolyle, triazolyle, oxadiazolyle, thiadiazolyle, pyridinyle, pyridazinyle, pyrimidinyle ou pyridazinyle, et est substitué par 0 à 3 substituants choisis parmi un halogène, alkyle, halogénoalkyle, alkoxy, halogénoalkoxy, phényle et benzyloxy ;
    ou un de ses sels pharmaceutiquement acceptables.
  2. Composé selon la revendication 1, dans lequel :
    R1 est un alkyle ;
    R2 est un phényle ou pyridinyle et est substitué par 1 substituant choisi parmi un alkoxy, (Ar1)O et (Ar1)alkoxy, et est aussi substitué par 0 à 3 substituants choisis parmi un halogène, alkyle, halogénoalkyle, alkoxy et halogénoalkoxy ;
    R3 est un azétidinyle, pyrrolidinyle, pipéridinyle, pipérazinyle, morpholinyle, homopipéridinyle, homopipérazinyle, ou homomorpholinyle, et est substitué par 0 à 3 substituants choisis parmi un halogène, alkyle, halogénoalkyle, alkoxy, et halogénoalkoxy ;
    R4 est un alkyle ou halogénoalkyle ;
    R5 est un alkyle ; et
    Ar1 est un phényle substitué par 0 à 3 substituants choisis parmi un halogène, alkyle, halogénoalkyle, alkoxy, et halogénoalkoxy ;
    ou un de ses sels pharmaceutiquement acceptables.
  3. Composé selon la revendication 2, dans lequel R1 est un alkyle ; R2 est un phényle ou pyridinyle et est substitué par 1 substituant choisi parmi un alkoxy, (Ar1)O ou (Ar1)alkoxy, et est aussi substitué par 0 à 3 substituants choisis parmi un halogène, alkyle, halogénoalkyle, alkoxy et halogénoalkoxy ; R3 est un pipéridinyle substitué par 0 à 3 substituants alkyle ; R4 est un alkyle ; R5 est un alkyle ; et Ar1 est un phényle substitué par 0 à 3 substituants choisis parmi un halogène, alkyle, halogénoalkyle, alkoxy, et halogénoalkoxy ; ou un de ses sels pharmaceutiquement acceptables.
  4. Composé selon la revendication 1, dans lequel R2 est un phényle substitué par 1 substituant choisi parmi un alkoxy, (Ar1)O ou (Ar1) alkoxy, et est aussi substitué par 0 à 3 substituants choisis parmi un halogène, alkyle, halogénoalkyle, alkoxy et halogénoalkoxy.
  5. Composé selon la revendication 1, dans lequel R3 est un pipéridinyle substitué par 0 à 3 substituants choisis parmi un cyano, halogène, alkyle, halogénoalkyle, cycloalkyle, halogénocycloalkyle, alcényle, alkoxy, halogénoalkoxy, CON(R6)(R7), phényle, benzyle et (alkyl) oxadiazolyle.
  6. Composé selon la revendication 5, dans lequel R3 est un pipéridinyle, géminalement disubstitué en position 4 par 2 substituants choisis parmi un cyano, halogène, alkyle, halogénoalkyle, cycloalkyle, halogénocycloalkyle, alcényle, alkoxy, halogénoalkoxy, CON(R6)(R7), phényle, benzyle ou (alkyl)oxadiazolyle.
  7. Composé selon la revendication 1, choisi dans le groupe constitué de :
    l'acide (S)-2-(tert-butoxy)-2-(4-(4,4-diméthylpipéridine-1-yl)-2,6-diméthyl-5-(4-phénoxyphényl)pyridine-3-yl)acétique ;
    l'acide (S)-2-(tert-butoxy)-2-(4-(4,4-diméthylpipéridine-1-yl)-5-(4-((4-fluorobenzyl)oxy)phényl)-2,6-diméthylpyridine-3-yl)acétique ;
    l'acide (S)-2-(6'-(benzyloxy)-4-(4,4-diméthylpipéridine-1-yl)-2,6-diméthyl-[3,3'-bipyridine]-5-yl)-2-(tert-butoxy)-acétique ;
    l'acide (S)-2-(5-(4-(benzyloxy)-3-fluorophényl)-4-(4,4-diméthylpipéridine-1-yl)-2,6-diméthylpyridine-3-yl)-2-(tert-butoxy)acétique ;
    l'acide (S)-2-(5-(4-(benzyloxy)phényl)-4-(4,4-diméthylpipéridine-1-yl)-2,6-diméthylpyridine-3-yl)-2-(tert-butoxy)-acétique ;
    l'acide (S)-2-(tert-butoxy)-2-(4-(4,4-diméthylpipéridine-1-yl)-5-(4-éthoxyphényl)-2,6-diméthylpyridine-3-yl)acétique ;
    l'acide (S)-2-(tert-butoxy)-2-(4-(4,4-diméthylpipéridine-1-yl)-5-(4-(4-fluorophénéthoxy)phényl)-2,6-diméthylpyridine-3-yl)acétique ;
    l'acide (S)-2-(tert-butoxy)-2-(4-(4,4-diméthylpipéridine-1-yl)-5-(4-(4-fluoro-3-méthylphénéthoxy)phényl)-2,6-diméthylpyridine-3-yl)acétique ;
    l'acide (S)-2-(tert-butoxy)-2-(4-(4,4-diméthylpipéridine-1-yl)-5-(4-(3-(4-fluorophényl)propoxy)phényl)-2,6-diméthylpyridine-3-yl)acétique ;
    l'acide (S)-2-(tert-butoxy)-2-(5-(4-(3,3-diméthylbutoxy)-phényl)-4-(4,4-diméthylpipéridine-1-yl)-2,6-diméthylpyridine-3-yl)acétique ;
    l'acide (S)-2-(tert-butoxy)-2-(4-(4,4-diméthylpipéridine-1-yl)-5-(4-(4-méthoxyphénéthoxy)phényl)-2,6-diméthylpyridine-3-yl)acétique ;
    l'acide (S)-2-(tert-butoxy)-2-(4-(4,4-diméthylpipéridine-1-yl)-5-(4-hydroxyphényl)-2,6-diméthylpyridine-3-yl)acétique ;
    l'acide (S)-2-(tert-butoxy)-2-(5-(4-(4-carbamoyl-phénéthoxy)-phényl)-4-(4,4-diméthylpipéridine-1-yl)-2,6-diméthylpyridine-3-yl)acétique ;
    l'acide (S)-2-(tert-butoxy)-2-(5-(4-(4-cyano-phénéthoxy)-phényl)-4-(4,4-diméthylpipéridine-1-yl)-2,6-diméthylpyridine-3-yl)acétique ;
    l'acide (S)-2-(tert-butoxy)-2-(5-(4-((4-carbamoylbenzyl)-oxy)phényl)-4-(4,4-diméthylpipéridine-1-yl)-2,6-diméthylpyridine-3-yl)acétique ;
    l'acide (S)-2-(tert-butoxy)-2-(5-(4-((4-cyanobenzyl)-oxy)phényl)-4-(4,4-diméthylpipéridine-1-yl)-2,6-diméthylpyridine-3-yl)acétique ;
    l'acide (2S)-2-(tert-butoxy)-2-(4-(4,4-diméthylpipéridine-1-yl)-(5-(4-((1-(4-fluorophényl)propane-2-yl)oxy)phényl)-2,6-diméthylpyridine-3-yl)acétique ;
    l'acide (2S)-2-(tert-butoxy)-2-(4-(4,4-diméthylpipéridine-1-yl)-(5-(4-((1-(4-fluorophényl)propane-2-yl)oxy)phényl)-2,6-diméthylpyridine-3-yl)acétique ;
    l'acide (S)-2-(tert-butoxy)-2-(5-(4-(2,4-difluorophénéthoxy)phényl)-4-(4,4-diméthylpipéridine-1-yl)-2,6-diméthylpyridine-3-yl)acétique ;
    l'acide (S)-2-(tert-butoxy)-2-(5-(4-(3,4-difluorophénéthoxy)phényl)-4-(4,4-diméthylpipéridine-1-yl)-2,6-diméthylpyridine-3-yl)acétique ;
    l'acide (S)-2-(tert-butoxy)-2-(5-(4-(2,5-difluorophénéthoxy)phényl)-4-(4,4-diméthylpipéridine-1-yl)-2,6-diméthylpyridine-3-yl)acétique ;
    l'acide (S)-2-(tert-butoxy)-2-(5-(4-(4-chlorophénéthoxy)-phényl)-4-(4,4-diméthylpipéridine-1-yl)-2,6-diméthylpyridine-3-yl)acétique ;
    l'acide (S)-2-(tert-butoxy)-2-(5-(4-(4-chloro-3-fluorophénéthoxy)phényl)-4-(4,4-diméthylpipéridine-1-yl)-2,6-diméthylpyridine-3-yl)acétique ;
    l'acide (S)-2-(tert-butoxy)-2-(4-(4,4-diméthylpipéridine-1-yl)-2,6-diméthyl-5-(4-(4-méthylphénéthoxy)-phényl)pyridine-3-yl)acétique ;
    l'acide (S)-2-(tert-butoxy)-2-(5-(4-(2-(4-chlorophényl)-2-méthylpropoxy)phényl)-4-(4,4-diméthylpipéridine-1-yl)-2,6-diméthylpyridine-3-yl)acétique ;
    l'acide (S)-2-(tert-butoxy)-2-(4-(4,4-diméthylpipéridine-1-yl)-2,6-diméthyl-5-(4-(2-(naphtalène-2-yl)éthoxy)phényl)-pyridine-3-yl)acétique ;
    l'acide (S)-2-(5-(4-(4-(benzyloxy)phénéthoxy)phényl)-4-(4,4-diméthylpipéridine-1-yl)-2,6-diméthylpyridine-3-yl)-2-(tert-butoxy)acétique ;
    l'acide (2S)-2-(tert-butoxy)-2-(4-(4,4-diméthylpipéridine-1-yl)-5-(4-(2-(4-fluorophényl)propoxy)phényl)-2,6-diméthylpyridine-3-yl)acétique ;
    l'acide (S)-2-(tert-butoxy)-2-(4-(4,4-diméthylpipéridine-1-yl)-2,6-diméthyl-5-(4-(2-(pyridine-2-yl)éthoxy)phényl)pyridine-3-yl)acétique ;
    l'acide (S)-2-(tert-butoxy)-2-(4-(4,4-diméthylpipéridine-1-yl)-5-(4-((S)-2-méthoxy-2-phényléthoxy)phényl)-2,6-diméthylpyridine-3-yl)acétique ;
    l'acide (S)-2-(tert-butoxy)-2-(4-(4,4-diméthylpipéridine-1-yl)-5-(4-((R)-2-méthoxy-2-phényléthoxy)phényl)-2,6-diméthylpyridine-3-yl)acétique ;
    l'acide (S)-2-(tert-butoxy)-2-(-4-(4,4-diméthylpipéridine-1-yl)-5-(4-(3-méthoxyphénéthoxy)phényl)-2,6-diméthylpyridine-3-yl)acétique ;
    l'acide (S)-2-(tert-butoxy)-2-(4-(4,4-diméthylpipéridine-1-yl)-2,6-diméthyl-5-(4-(2-(pyridine-4-yl)éthoxy)phényl)pyridine-3-yl)acétique ;
    l'acide (S)-2-(tert-butoxy)-2-(4-(4,4-diméthylpipéridine-1-yl)-2,6-diméthyl-5-(4-(2-(naphtalène-1-yl)éthoxy)phényl)-pyridine-3-yl)acétique ;
    l'acide (S)-2-(tert-butoxy)-2-(4-(4,4-diméthylpipéridine-1-yl)-2,6-diméthyl-5-(4-phénéthoxyphényl)pyridine-3-yl)acétique ;
    l'acide (S)-2-(tert-butoxy)-2-(4-(4,4-diméthylpipéridine-1-yl)-2,6-diméthyl-5-(4-(2-(4-méthylthiazole-5-yl)éthoxy)-phényl)pyridine-3-yl)acétique ;
    l'acide (S)-2-(tert-butoxy)-2-(4-(4,4-diméthylpipéridine-1-yl)-2,6-diméthyl-5-(4-(2-(pyridine-3-yl)éthoxy)phényl)pyridine-3-yl)acétique ;
    l'acide (S)-2-(tert-butoxy)-2-(4-(4,4-diméthylpipéridine-1-yl)-2,6-diméthyl-5-(4-(2-(2-méthylthiazole-4-yl)éthoxy)-phényl)pyridine-3-yl)acétique ;
    l'acide (S)-2-(tert-butoxy)-2-(4-(4,4-diméthylpipéridine-1-yl)-2,6-diméthyl-5-(4-(thiazole-5-yl)méthoxy)phényl)pyridine-3-yl)acétique ;
    l'acide (S)-2-(tert-butoxy)-2-(4-(4,4-diméthylpipéridine-1-yl)-5-(4-((2,4-diméthylthiazole-5-yl)méthoxy)phényl)-2,6-diméthylpyridine-3-yl)acétique ;
    l'acide (S)-2-(tert-butoxy)-2-(4-(4,4-diméthylpipéridine-1-yl)-2,6-diméthyl-5-(4-((4-méthyl-2-phényl-thiazole-5-yl)-méthoxy)phényl)pyridine-3-yl)acétique ;
    l'acide (S)-2-(5-(3,4-bis(3-méthoxyphénéthoxy)phényl)-4-(4,4-diméthylpipéridine-1-yl)-2,6-diméthylpyridine-3-yl)-2-(tert-butoxy)acétique ;
    l'acide (S)-2-(tert-butoxy)-2-(5-(4-((2-chlorothiazole-5-yl)méthoxy)phényl)-4-(4,4-diméthylpipéridine-1-yl)-2,6-diméthylpyridine-3-yl)acétique ;
    l'acide (S)-2-(tert-butoxy)-2-(4-(4,4-diméthylpipéridine-1-yl)-5-(4-(2-(2,4-diméthylthiazole-5-yl)éthoxy)phényl)-2,6-diméthylpyridine-3-yl)acétique ;
    l'acide (S)-2-(tert-butoxy)-2-(4-(4,4-diméthylpipéridine-1-yl)-5-(4-(2-(4-fluorophényl)-2-méthyl-propoxy)phényl)-2,6-diméthylpyridine-3-yl)acétique ;
    l'acide (S)-2-(tert-butoxy)-2-(4-(4,4-diméthylpipéridine-1-yl)-2,6-diméthyl-5-(4-(2,4,5-trifluoro-phénéthoxy)phényl)-pyridine-3-yl)acétique ;
    l'acide (S)-2-(tert-butoxy)-2-(4-(4,4-diméthylpipéridine-1-yl)-2,6-diméthyl-5-(4-(2,3,5,6-tétrafluoro-phénéthoxy)-phényl)pyridine-3-yl)acétique ;
    l'acide (S)-2-(tert-butoxy)-2-(4-(4,4-diméthylpipéridine-1-yl)-2,6-diméthyl-5-(4-(2-(5-méthylthiophène-2-yl)éthoxy)-phényl)pyridine-3-yl)acétique ;
    l'acide (S)-2-(tert-butoxy)-2-(5-(4-(2-(3,5-diméthyl-isoxazole-4-yl)éthoxy)phényl)-4-(4,4-diméthylpipéridine-1-yl)-2,6-diméthylpyridine-3-yl)acétique ;
    l'acide (S)-2-(tert-butoxy)-2-(5-(4-(2-(3,5-diméthyl-1H-pyrazole-4-yl)éthoxy)phényl)-4-(4,4-diméthylpipéridine-1-yl)-2,6-diméthylpyridine-3-yl)acétique ;
    l'acide (S)-2-(5-(3-(benzyloxy)-4-méthylphényl)-4-(4,4-diméthylpipéridine-1-yl)-2,6-diméthylpyridine-3-yl)-2-(tert-butoxy)acétique ;
    l'acide (S)-2-(tert-butoxy)-2-(4-(4,4-diméthylpipéridine-1-yl)-2,6-diméthyl-5-(4-(pyridine-4-yl)méthoxy)phényl)pyridine-3-yl)acétique ;
    l'acide (S)-2-(tert-butoxy)-2-(4-(4,4-diméthylpipéridine-1-yl)-5-(2-méthoxypyrimidine-5-yl)-2,6-diméthylpyridine-3-yl)-acétique ;
    l'acide (S)-2-(tert-butoxy)-2-(4-(4,4-diméthylpipéridine-1-yl)-5-(2-(4-fluorophénéthoxy)pyrimidine-5-yl)-2,6-diméthylpyridine-3-yl)acétique ;
    l'acide (S)-2-(tert-butoxy)-2-(4-(4,4-diméthylpipéridine-1-yl)-5-(3-fluoro-4-propoxyphényl)-2,6-diméthylpyridine-3-yl)-acétique ;
    l'acide (S)-2-(tert-butoxy)-2-(4-(4,4-diméthylpipéridine-1-yl)-2,6-diméthyl-5-(3,4,5-triméthoxy-phényl)pyridine-3-yl)-acétique ;
    l'acide (S)-2-(tert-butoxy)-2-(4-(4,4-diméthylpipéridine-1-yl)-5-(3-méthoxy-4-méthylphényl)-2,6-diméthylpyridine-3-yl)-acétique ;
    l'acide (S)-2-(tert-butoxy)-2-(4-(4,4-diméthylpipéridine-1-yl)-5-(3-méthoxyphényl)-2,6-diméthylpyridine-3-yl)acétique ;
    l'acide (S)-2-(tert-butoxy)-2-(5-(3-chloro-4-isopropoxyphényl)-4-(4,4-diméthylpipéridine-1-yl)-2,6-diméthylpyridine-3-yl)acétique ;
    l'acide (S)-2-(tert-butoxy)-2-(5-(3,5-diméthyl-4-propoxyphényl)-4-(4,4-diméthylpipéridine-1-yl)-2,6-diméthylpyridine-3-yl)acétique ;
    l'acide (S)-2-(tert-butoxy)-2-(4-(4,4-diméthylpipéridine-1-yl)-5-(4-éthoxy-3-fluorophényl)-2,6-diméthylpyridine-3-yl)-acétique ;
    l'acide (S)-2-(tert-butoxy)-2-(4-(4,4-diméthylpipéridine-1-yl)-5-(4-fluoro-3-méthoxyphényl)-2,6-diméthylpyridine-3-yl)-acétique ;
    l'acide (S)-2-(tert-butoxy)-2-(4-(4,4-diméthylpipéridine-1-yl)-6'-(4-fluorophénéthoxy)-2,6-diméthyl-[3,3'-bipyridine]-5-yl)acétique ;
    l'acide (S)-2-(tert-butoxy)-2-(4-(3-cyclopropyl-pyrrolidine-1-yl)-5-(4-(4-fluorophénéthoxy)phényl)-2,6-diméthylpyridine-3-yl)acétique ;
    l'acide (S)-2-(tert-butoxy)-2-(4-(3,3-difluoroazétidine-1-yl)-5-(4-(4-fluorophénéthoxy)phényl)-2,6-diméthylpyridine-3-yl)acétique ;
    l'acide (S)-2-(tert-butoxy)-2-(4-(3,3-diméthylazétidine-1-yl)-5-(4-(4-fluorophénéthoxy)phényl)-2,6-diméthylpyridine-3-yl)acétique ;
    l'acide (S)-2-(tert-butoxy)-2-(5-(4-(4-fluorophénéthoxy)-phényl)-4-(3-isopropylazétidine-1-yl)-2,6-diméthylpyridine-3-yl)acétique ;
    l'acide (S)-2-(tert-butoxy)-2-(5-(4-(4-fluorophénéthoxy)-phényl)-2,6-diméthyl-4-(4-phénylpipéridine-1-yl)pyridine-3-yl)-acétique ;
    l'acide (S)-2-(tert-butoxy)-2-(5-(4-(4-fluorophénéthoxy)-phényl)-4-(4-(3-isopropyl-1,2,4-oxadiazole-5-yl)pipéridine-1-yl)-2,6-diméthylpyridine-3-yl)acétique ;
    l'acide (S)-2-(tert-butoxy)-2-(5-(4-(4-fluorophénéthoxy)-phényl)-2,6-diméthyl-(4-(4-(trifluorométhyl)-pipéridine-1-yl)pyridine-3-yl)acétique ;
    l'acide (S)-2-(tert-butoxy)-2-(4-(4-éthyl-4-méthylpipéridine-1-yl)-5-(4-(4-fluorophénéthoxy)phényl)-2,6-diméthylpyridine-3-yl)acétique ;
    l'acide (S)-2-(tert-butoxy)-2-(5-(4-(4-fluorophénéthoxy)-phényl)-2,6-diméthyl-4-(4-méthylpipéridine-1-yl)pyridine-3-yl)acétique ;
    l'acide (S)-2-(tert-butoxy)-2-(5-(4-(4-fluorophénéthoxy)-phényl)-4-(4-méthoxy-4-méthylpipéridine-1-yl)-2,6-diméthylpyridine-3-yl)acétique ;
    l'acide (S)-2-(tert-butoxy)-2-(4-(4-cyano-4-méthylpipéridine-1-yl)-5-(4-(4-fluorophénéthoxy)phényl)-2,6-diméthylpyridine-3-yl)acétique ;
    l'acide (S)-2-(tert-butoxy)-2-(5-(4-(4-fluorophénéthoxy)-phényl)-2,6-diméthyl-4-(4-(propane-2-ylidène)-pipéridine-1-yl)pyridine-3-yl)acétique ;
    l'acide (S)-2-(4-(4-benzylpipéridine-1-yl)-5-(4-(4-fluorophénéthoxy)phényl)-2,6-diméthylpyridine-3-yl)-2-(tert-butoxy)-acétique ;
    l'acide (S)-2-(tert-butoxy)-2-(4-(4-fluoro-4-méthylpipéridine-1-yl)-5-(4-(4-fluorophénéthoxy)phényl)-2,6-diméthylpyridine-3-yl)acétique ; et
    l'acide (S)-2-(tert-butoxy)-2-(4-((3,5-diméthylpipéridine-1-yl)-5-(4-(4-fluorophénéthoxy)phényl)-2,6-diméthylpyridine-3-yl)acétique ;
    ou un de leurs sels pharmaceutiquement acceptables.
  8. Composé selon la revendication 1, choisi dans le groupe constitué de :
    l'acide (S)-2-(tert-butoxy)-2-(4-(4,4-diméthylpipéridine-1-yl)-5-(4-((4-fluorobenzyl)oxy)phényl)-2,6-diméthylpyridine-3-yl)acétique ;
    l'acide (S)-2-(tert-butoxy)-2-(4-(4,4-diméthylpipéridine-1-yl)-5-(4-((4-méthoxybenzyl)oxy)phényl)-2,6-diméthylpyridine-3-yl)acétique ;
    l'acide (S)-2-(tert-butoxy)-2-(4-(4,4-diméthylpipéridine-1-yl)-5-(4-(4-fluorophénéthoxy)phényl)-2,6-diméthylpyridine-3-yl)acétique ;
    l'acide (S)-2-(tert-butoxy)-2-(4-(4,4-diméthylpipéridine-1-yl)-5-(4-(4-fluoro-3-méthylphénéthoxy)phényl)-2,6-diméthylpyridine-3-yl)acétique ;
    l'acide (S)-2-(tert-butoxy)-2-(5-(4-(2,4-difluorophénéthoxy)phényl)-4-(4,4-diméthylpipéridine-1-yl)-2,6-diméthylpyridine-3-yl)acétique ;
    l'acide (2S)-2-(tert-butoxy)-2-(4-(4,4-diméthylpipéridine-1-yl)-(5-(4-((1-(4-fluorophényl)propane-2-yl)oxy)phényl)-2,6-diméthylpyridine-3-yl)acétique ;
    l'acide (S)-2-(tert-butoxy)-2-(4-(4,4-diméthylpipéridine-1-yl)-2,6-diméthyl-5-(4-(2-(pyridine-4-yl)éthoxy)phényl)pyridine-3-yl)acétique ;
    l'acide (S)-2-(tert-butoxy)-2-(4-(4,4-diméthylpipéridine-1-yl)-2,6-diméthyl-5-(4-(2-(4-méthylthiazole-5-yl)éthoxy)phényl)-pyridine-3-yl)acétique ;
    l'acide (S)-2-(tert-butoxy)-2-(4-(4,4-diméthypipéridine-1-yl)-5-(4-(2-(2,4-diméthylthiazole-5-yl)éthoxy)phényl)-2,6-diméthylpyridine-3-yl)acétique ;
    l'acide (S)-2-(tert-butoxy)-2-(4-(4,4-diméthylpipéridine-1-yl)-5-(4-(2-(4-fluorophényl)-2-méthyl-propoxy)phényl)-2,6-diméthylpyridine-3-yl)acétique ;
    l'acide (S)-2-(tert-butoxy)-2-(4-(4-éthyl-4-méthylpipéridine-1-yl)-5-(4-(4-fluorophénéthoxy)phényl)-2,6-diméthylpyridine-3-yl)acétique ;
    l'acide (S)-2-(tert-butoxy)-2-(5-(4-(2-(3,5-diméthylisoxazole-4-yl)éthoxy)phényl)-4-(4,4-diméthylpipéridine-1-yl)-2,6-diméthylpyridine-3-yl)acétique ;
    l'acide (S)-2-(tert-butoxy)-2-(4-(4-fluoro-4-méthylpipéridine-1-yl)-5-(4-(4-fluorophénéthoxy)phényl)-2,6-diméthylpyridine-3-yl)acétique ;
    ou un de leurs sels pharmaceutiquement acceptables.
  9. Composition utile pour le traitement de l'infection par le VIH, comprenant une quantité thérapeutique d'un composé selon l'une quelconque des revendications 1 à 8 et un véhicule acceptable pharmaceutiquement.
  10. Composition selon la revendication 9, comprenant en outre au moins un autre agent utilisé pour le traitement du SIDA ou de l'infection par le VIH choisi dans le groupe constitué des inhibiteurs de transcriptase inverse du VIH nucléosidiques, des inhibiteurs de transcriptase inverse du VIH non nucléosidiques, des inhibiteurs de protéase du VIH, des inhibiteurs de fusion du VIH, des inhibiteurs d'attachement du VIH, des inhibiteurs de CCR5, des inhibiteurs de CXCR4, des inhibiteurs de bourgeonnement ou de maturation du VIH, et des inhibiteurs d'intégrase du VIH.
  11. Composé selon l'une quelconque des revendications 1 à 8 ou un de ses sels pharmaceutiquement acceptables pour utilisation dans le traitement de l'infection par le VIH.
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